Genome-wide haplotype association study identifies the FRMD4A gene as a risk locus for Alzheimer's disease
Open accessAbstract
Recently, several genome-wide association studies (GWASs) have led to the discovery of nine new loci of genetic susceptibility in Alzheimer's disease (AD). However, the landscape of the AD genetic susceptibility is far away to be complete and in addition to single-SNP (single-nucleotide polymorphism) analyses as performed in conventional GWAS, complementary strategies need to be applied to overcome limitations inherent to this type of approaches. We performed a genome-wide haplotype association (GWHA) study in the EADI1 study (n=2025 AD cases and 5328 controls) by applying a sliding-windows approach. After exclusion of loci already known to be involved in AD (APOE, BIN1 and CR1), 91 regions with suggestive haplotype effects were identified. In a second step, we attempted to replicate the best suggestive haplotype associations in the GERAD1 consortium (2820 AD cases and 6356 controls) and observed that 9 of them showed nominal association. In a third step, we tested relevant haplotype associations in a combined analysis of five additional case-control studies (5093 AD cases and 4061 controls). We consistently replicated the association of a haplotype within FRMD4A on Chr.10p13 in all the data set analyzed (OR: 1.68; 95% CI: (1.43-1.96); P=1.1 × 10(-10)). We finally searched for association between SNPs within the FRMD4A locus and Aβ plasma concentrations in three independent non-demented populations (n=2579). We reported that polymorphisms were associated with plasma Aβ42/Aβ40 ratio (best signal, P=5.4 × 10(-7)). In conclusion, combining both GWHA study and a conservative three-stage replication approach, we characterised FRMD4A as a new genetic risk factor of AD.
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A genome-wide haplotype association analysis in populations of European descent identified new AD risk haplotypes in the FRMD4A locus.
“For example, a genome-wide haplotype association analysis in populations of European descent identified new AD risk haplotypes in the FRMD4A locus [47].”
From Association of SPI1 haplotypes with altered SPI1 gene expression and Alzheimer’s disease risk (2022) · cites this paper as [47]
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- Authors
- EADI consortium, G. C., Lambert, J.-C., Grenier-Boley, B., Harold, D., Zelenika, D., Chouraki, V, Kamatani, Y., Sleegers, K., Ikram, M. A., Hiltunen, M., Reitz, C., Mateo, I., Feulner, T., Bullido, M., Galimberti, D., Concari, L., Alvarez, V, Sims, R., Gerrish, A., Chapman, J., Deniz-Naranjo, C., Solfrizzi, V, Sorbi, S., Arosio, B., Spalletta, G., Siciliano, G., Epelbaum, J., Hannequin, D., Dartigues, J.-F., Tzourio, C., Berr, C., Schrijvers, E. M. C., Rogers, R., Tosto, G., Pasquier, F., Bettens, K., Van Cauwenberghe, C., Fratiglioni, L., Graff, C., Delepine, M., Ferri, R., Reynolds, C. A., Lannfelt, L., Ingelsson, M., Prince, J. A., Chillotti, C., Pilotto, A., Seripa, D., Boland, A., Mancuso, M., Bossù, P., Annoni, G., Nacmias, B., Bosco, P., Panza, F., Sanchez-Garcia, F., Del Zompo, M., Coto, E., Owen, M., O'Donovan, M., Valdivieso, F., Caffara, P., Scarpini, E., Combarros, O., Buée, L., Campion, D., Soininen, H., Breteler, M., Riemenschneider, M., Van Broeckhoven, C., Alpérovitch, A., Lathrop, M., Trégouët, D.-A., Williams, J., & Amouyel, P.
- Affiliations
- Inserm (FR)
- Cardiff University (GB)
- Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
- University of Antwerp (BE)
- Erasmus MC (NL)
- University of Eastern Finland (FI)
- Columbia University (US)
- Universidad de Cantabria (ES)
- Universitätsklinikum des Saarlandes (DE)
- Biomedical Research Networking Center on Neurodegenerative Diseases (ES)
- University of Milan (IT)
- University of Parma (IT)
- Hospital Universitario de Gran Canaria Doctor Negrín (ES)
- University of Bari Aldo Moro (IT)
- University of Florence (IT)
- Fondazione Santa Lucia (IT)
- University of Pisa (IT)
- Centre Hospitalier Universitaire de Lille (FR)
- Karolinska University Hospital (SE)
- Oasi Maria SS (IT)
- University of California, Riverside (US)
- Uppsala University (SE)
- Karolinska Institutet (SE)
- University of Cagliari (IT)
- Casa Sollievo della Sofferenza (IT)
- Hospital Universitario Central de Asturias (ES)
- German Center for Neurodegenerative Diseases (DE)
- Corresponding author
- Lambert, J-C
- ORCID
- Lambert, J-C
- Harold, D
- Chouraki, V
- Sleegers, K
- Ikram, M A
- Hiltunen, M
- Bullido, M
- Galimberti, D
- Concari, L
- Sims, R
- Gerrish, A
- Chapman, J
- Solfrizzi, V
- Sorbi, S
- Arosio, B
- Spalletta, G
- Siciliano, G
- Hannequin, D
- Dartigues, J-F
- Tzourio, C
- Berr, C
- Rogers, R
- Tosto, G
- Pasquier, F
- Fratiglioni, L
- Graff, C
- Ferri, R
- Reynolds, C A
- Lannfelt, L
- Ingelsson, M
- Chillotti, C
- Seripa, D
- Boland, A
- Mancuso, M
- Bossù, P
- Annoni, G
- Nacmias, B
- Bosco, P
- Panza, F
- Coto, E
- Owen, M
- Scarpini, E
- Buée, L
- Campion, D
- Soininen, H
- Breteler, M
- Riemenschneider, M
- Lathrop, M
- Trégouët, D-A
- Williams, J
- Amouyel, P
- Venue
- Molecular Psychiatry
- Published
- 2012-03-20
- Volume
- 18
- Issue
- 4
- Pages
- 461-470
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC3606943
- OpenAlex
- W2138023910
- Cited by
- 129
- References
- 4
- Citations by year
- 2026: 2 · 2025: 9 · 2024: 18 · 2023: 4 · 2022: 13 · 2021: 7 · 2020: 9 · 2019: 10 · 2018: 8 · 2017: 10 · 2016: 12 · 2015: 6 · 2014: 7 · 2013: 12 · 2012: 2
- FWCI
- 5.79
- Type
- journal article
- Language
- en
- Update notices
- erratum (2012-09-18)
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Psychiatry (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
- HAL (submittedVersion, cc-by-nc-sa)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion)
- BOA (University of Milano-Bicocca) (submittedVersion, cc-by-nc-sa)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- Florence Research (University of Florence) (submittedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- UNICA IRIS Institutional Research Information System (University of Cagliari) (submittedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- DZNE Pub (submittedVersion)
- CINECA IRIS Institutional Research Information System (University of Bari Aldo Moro) (submittedVersion)
- Funders
- Institut National de la Santé et de la Recherche Médicale
- Medical Research Council (MR/K013041/1)
- National Institute on Aging (R01AG004563, AG-10175, AG04563, K23AG034550, AG 08724, AG028555, R01AG028555, AG 08861, R01AG010175, R01AG008724)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- Alzheimer's disease, haplotype association, genetic susceptibility, amyloid-beta 42/40 ratio, plasma amyloid-beta, single nucleotide polymorphisms
- MeSH terms
- Alzheimer Disease, Haplotypes, Humans, Case-Control Studies, Amyloid beta-Peptides, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Adaptor Proteins, Signal Transducing, Genome-Wide Association Study
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